The sodium channels open very rapidly, or activate (in ≈0.1 msec), thereby resulting in an abrupt increase in gNa. However, once open, the sodium channels inactivate (time course ≅ 1 to 2 msec), and gNa rapidly decreases (Fig. 16.3 ). The sodium channels remain in the inactivated state until the membrane begins to repolarize. With repolarization, the channel transitions to the closed state, from which it can then be reopened by another depolarization of Vm to the threshold. These properties of the sodium channel are the basis of the refractory period of the action potential. When the sodium channels are in the inactivated state, they cannot be reopened, and another action potential cannot be generated. During this period, the cell is said to be in the effective refractory period. This prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell repolarizes (phase 3), the inactivated channels begin to transition to the closed state. During this period, called the relative refractory period, another action potential can be generated, but it requires a larger-than-normal depolarization of Vm. Only when Vm has returned to the resting level (phase 4) are all the sodium channels closed and thus able to be reactivated by the normal depolarization of Vm.
Anioniccurrentthroughonemembranechannelcanbemeasuredwiththepatchclamptechnique.Theindividualchannelsopenandcloserepeatedlyinarandommanner.Thisprocessisillustratedin
Fig.16.4 ,whichshowsthecurrentflowthroughsodiumchannelsinamyocardialcell.Beforethetimeindicatedbythearrow,themembranepotentialwasclampedat−85mV.Atthetimeindicatedbythearrow,thepotentialwassuddenlychangedto−45mV,atwhichvalueitwasheldfortheremainderoftherecording.
Fig.16.4 indicatesthatimmediatelyafterthemembranepotentialwasmadelessnegative,onesodiumchannelopened(1.5pAinamplitude),andthenasecondsodiumchannelopened(3pAtotalcurrentfrombothchannels),whereuponbothchannelsclosed(i.e.,thecurrentreturnedto0).Bothchannelsclosedforapproximately4or5msec,andthenbothchannelsopenedatthesametime.Thereafter,onechannelclosedandthenthesecondrapidlyclosed.Finally,afterseveralseconds,onechannelopenedandthenclosed.Thereafter,bothchannelsremainedclosedfortherestoftherecording,eventhoughthemembranevoltagewasheldconstantat−45mV.
Genesis of Early Repolarization (Phase 1)
In many cardiac cells that have a prominent plateau, phase 1 is an early, brief period of limited repolarization. This brief repolarization results in the notch between the end of the upstroke and the beginning of the plateau (see
Figs. 16.1 16.3).
Repolarization is brief because of activation of a transient outward current (ito) carried mainly by K+ . Activation of potassium channels during phase 1 causes a brief efflux of K+ from the cell because the cell interior is positively charged and intracellular [K+] greatly exceeds extracellular [K+] (see
Fig. 16.3 ). The cell is briefly and partially repolarized as a result of this transient efflux of K+ .
The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall (
Fig. 16.5 ) and in ventricular Purkinje fibers. However, the notch is negligible in myocytes from the endocardial region of the left ventricle (see